KR102171570B1 - Process for producing cellulose derivatives of high bulk density, good flowability and/or dispersibility in cold water as well as low solution color - Google Patents

Abstract

The particulate cellulose derivative comprises: A) providing a cellulose derivative having a moisture content of 60 to 95%, based on the total weight of the wet cellulose derivative, B) grinding and parting the wet cellulose derivative in a gas-injection impact mill. Drying, C) contacting the pulverized and partially dried cellulose derivative with an additional amount of dry gas outside the gas-injection impact mill, and D) contacting the cellulose derivative with a dry gas in step C). It is obtained by a pulverization and drying process of a wet cellulose derivative, comprising the step of partially depolymerizing the cellulose derivative afterwards. The obtained particulate cellulose derivative has a high uncompacted bulk density and good flowability and low color strength.

Description

Process for producing cellulose derivatives with high bulk density, good fluidity and/or excellent cold water dispersibility and weak solution color {PROCESS FOR PRODUCING CELLULOSE DERIVATIVES OF HIGH BULK DENSITY, GOOD FLOWABILITY AND/OR DISPERSIBILITY IN COLD WATER AS WELL AS LOW SOLUTION COLOR }

The present invention relates to particulate cellulose derivatives having high bulk density, good flowability and/or good cold water dispersibility and weak solution color, and methods of making such particulate cellulose derivatives.

Cellulose derivatives are of industrial importance and are used in a wide variety of technical fields and in a number of different end-use applications, such as the personal care or pharmaceutical industry, the agricultural sector, and the construction or oil industry. Its preparation, properties and fields of application are described, for example, in Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition, (1986), Volume A5, pages 461-488, VCH Verlagsgesellschaft, Weinheim; or "Methoden der organischen Chemie" (methods of organic chemistry), 4th Edition (1987), Volume E20, Makromolekulare Stoffe, Part Volume 3, pages 2048-2076, Georg Thieme Verlag, Stuttgart.

Water-soluble cellulose derivatives have found a wide range of uses. These water-soluble cellulose derivatives are conveniently supplied as dried particulate matter and then dissolved in water for the desired end use of these water-soluble cellulose derivatives.

It is preferable that the cellulose derivative has an appropriately high bulk density and excellent fluidity in order to facilitate transport and handling of the cellulose derivative.

Unfortunately, many water soluble cellulose derivatives are not dispersible in cold water. The non-dispersibility is due to the large surface area and fibrous nature of the cellulose derivative. The large surface area, when applied to water, allows external particles of the cellulose derivative to hydrate before the inside of the particles. In this way, around the inner particles, a gelatin film of hydrated outer particles is formed, preventing the inner particles from being completely hydrated. The first particles that come into contact with the water immediately swell and stick together, forming a gel-like barrier, preventing the remaining particles from hydrating. This gel-blocking behavior of water-soluble cellulose derivatives is a significant drawback in applications involving solutions of particulate water-soluble cellulose derivatives such as cellulose ethers in aqueous systems. The gel blocking behavior is visualized as the formation of "lumps," which require a long time for complete dissolution. In order to overcome this gel blocking behavior or the formation of lumps, the cellulose derivative is usually dispersed in hot water of about 80°C or higher. During shaking, the dispersion is cooled, and dissolution of the cellulose derivative occurs. At a certain temperature, the cellulose derivative dissolves and begins to increase in viscosity. This so-called hot/cold water dissolution technique takes advantage of the fact that water-soluble cellulose derivatives, such as cellulose ethers, are generally insoluble in hot water and soluble in cold water, depending on the type and degree of substitution. Unfortunately, this hot/cold water dissolution technique is very time consuming when an aqueous solution of the cellulose derivative has to be prepared. Thus, those skilled in the art have been working hard on methods of preparing cellulose derivatives that are dispersible in cold water, i.e. water below room temperature or water at room temperature or water slightly above room temperature without forming a significant amount of clumps. Various methods have been proposed such as temporary crosslinking with a dialdehyde such as glyoxal or treatment with a surfactant. However, these methods are not preferred for cellulose ethers in pharmaceutical or food applications. Other methods use additives such as tensides (surfactants) added to cellulose during manufacture (see US Pat. No. 7,361,753 B2), or additives such as salts, sugars, surfactants or low molecular weight water soluble polymers during the drying process. The use of surface coatings (see US Patent Application Publication No. 2007/0175361) is described.

In British patent specification GB 804,306, a wet mixture comprising 2 to 35% by weight of fibrous cold water soluble cellulose ether and 98 to 65% by weight of hot water is formed at a temperature above the gelation point of the cellulose ether, and the mixture is prepared, The fibrous structure is substantially dissipated and the material is cooled to below its gel point, e.g., 20° C., until the material becomes transparent, and the temperature is cooled to a temperature point at which syneresis occurs, e.g., 90 After raising to °C, the mixture is kept at a temperature point above the gelling point, for example, in an oven, and the dried product is, for example, 92% or more of the cellulose ether. A process of reducing to the desired particle size to pass through the mesh screen (corresponding to an opening of 354 μm) is described. However, this process takes too much time and energy to use on a large scale.

U.S. Patent No. 2,331,864 describes a method of treating fibrous cold water soluble cellulose ethers to improve their dissolution rate in cold water. In the process described above, after preparing a uniform slurry of 1 to 5% by weight of methylcellulose in hot water, for example, by removing excess water by pressurization or filtration under vacuum, 50°C or higher, preferably Sets the water content of the water-wet fibrous cellulose ether to a value of 72 to 88% by weight at a temperature of 70°C or higher. The wet material is cooled to a temperature of 50°C or less, preferably 5 to 23°C. The cooled material is aged until the desired degree of gel formation occurs, that is, the material becomes translucent and there are substantially no visible fibrous structures. The material is then immediately dried at a temperature above 50° C. by spreading it on a tray and blowing a stream of hot air thereon to bring it to a moisture content of less than 15%. The dried product is grinded. A product of 60 to 100 mesh fineness or finer is obtained, which is referred to as a free-flowing, non-caking powder, which easily dissolves when simply stirred with cold water. However, the process described above involves a number of steps and is time consuming. In addition, the 72 to 88% moisture content of the wet material appears to be sticky on a large scale and difficult to handle uniformly, as described in US Patent No. 2,331,864. Problems of plugging during partial drying on the tray described above will lead to inoperability in the manufacturing process, since large lump formation will hinder the transport of the material.

In international patent application WO 96/00748, an aqueous hydrated cellulose ether having a water content of 40 to 75% and a temperature of 40° C. or lower is extruded through a plurality of orifices having a cross-sectional area of 0.0075 to 1 mm 2, and thus strand-shaped elongated cellulose A process of forming an ether extrudate, drying it, and then cutting the elongated cellulose ether extrudate to the desired length is described. After drying the cellulose ether to a moisture content of about 25%, cutting can be performed in an air-swept impact mill (where hot air is blown across the mill). Although good water dispersible cellulose ether particles are achieved, unfortunately the process is large-scale due to high equipment cost when extruding the aqueous hydrous cellulose ether into strands and subsequently cutting them in an air-injection impact mill. It is not used as a furnace.

One aspect of the present invention is to provide cellulose derivatives having good flowability in combination with a suitably high untapped bulk density.

It is a preferred object of the present invention to provide cellulose derivatives which have good fluidity in combination with an appropriately high uncompacted bulk density and are well dispersed in cold water.

Another preferred object of the present invention is that it does not require time consuming steps such as drying in an oven or on a tray and subsequent grinding as described in British patent specification GB 804,306 and US patent 2,331,864, It is to provide a method for preparing the cellulose derivatives.

Another preferred object of the present invention is to provide a method for producing the cellulose derivatives, which extrudes the cellulose derivatives into strands and does not require cutting the strands as described in WO 96/00748.

Surprisingly, it has been found that the flowability and/or cold water dispersibility of the cellulose derivatives in particulate form can be improved by a novel process of grinding and drying the wet cellulose derivatives. Several processes for the combined drying and grinding of wet cellulose derivatives are described in patent application GB 2 262 527 A; EP 0 824 107 A2; EP-B 0 370 447 (corresponding to US Pat. No. 4,979,681); Although known in the art as described in EP 1 127 895 A1 (corresponding to US 2001/034441) and EP 0 954 536 A1 (corresponding to US Pat. No. 6,320,043), among these references None addressed the challenge of improving the cold water dispersibility of the cellulose derivative or provided evidence of good flowability of the cellulose derivative.

Pending patent application PCT/US12/031112 filed on March 29, 2012, based on the total weight of the wet cellulose derivative, the cellulose derivative having a moisture content of 25 to 95%, gas-injection impact mill pulverized and partially dried in a gas-swept impact mill, and the gas supplied to the impact mill has a temperature of 100° C. or less; The pulverized and partially dried cellulose derivative contains an additional amount of drying gas outside the gas-injection impact mill (wherein the drying gas has a higher temperature than the gas supplied into the impact mill) and Describe the contact process.

Cellulose derivatives used in the preparation of capsules or used in coating of dosage forms such as tablets are generally partially depolymerized, which is evident by the low viscosity of the derivatives as aqueous solutions. Cellulose derivatives having a viscosity of 2.4 to 200 mPa·s measured as a 2% by weight solution in water at 20° C. are commonly used in the preparation of capsules or in the coating of dosage forms such as tablets.

Pending patent application No. PCT/US12/031112 is described herein for drying and pulverizing partially depolymerized cellulose derivatives to obtain cellulose derivatives having high bulk density, good flowability and/or excellent cold water dispersibility. Illustrate the use of the method. In addition to high bulk density, good flowability and/or good cold water dispersibility, cellulose derivatives used in the manufacture of capsules or in coating of dosage forms, exhibit a weak color in solution to provide a light colored clean coating or capsule. It is very desirable to have. Unfortunately, drying and grinding of the partially depolymerized cellulose derivative increases the color intensity of the cellulose derivative due to impact and heating during drying and grinding.

The inventors of this patent application, surprisingly, improved the process described in pending patent application PCT/US12/031112, i) high bulk density, ii) weak solution color, and iii) good flowability and/or good cold water content. It has been found how an acidic dried and ground cellulose derivative is obtained.

One aspect of the present invention is a method of preparing a particulate cellulose derivative, the method comprising: A) providing a cellulose derivative having a moisture content of 25 to 95%, based on the total weight of the wet cellulose derivative; B) grinding and partially drying the wet cellulose derivative in a gas-injection impact mill, wherein the gas supplied into the impact mill has a temperature of 100°C or less; C) contacting the pulverized and partially dried cellulose derivative with an additional amount of dry gas outside the gas-injection impact mill (here, the additional amount of dry gas outside the gas-injection impact mill is the impact type) Has a higher temperature than the gas fed into the mill); And D) partially depolymerizing the cellulose derivative after contacting the cellulose derivative with a dry gas in step C).

Another aspect of the invention is a particulate cellulose derivative that can be prepared by the above-mentioned method.

Another aspect of the present invention is a method for improving the fluidity and/or dispersibility of the particulate cellulose derivative, wherein the method comprises: A) cellulose having a moisture content of 25 to 95% based on the total weight of the wet cellulose derivative. Providing a derivative; B) grinding and partially drying the wet cellulose derivative in a gas-injection impact mill, wherein the gas supplied into the impact mill has a temperature of 100°C or less; C) contacting the pulverized and partially dried cellulose derivative with an additional amount of dry gas outside the gas-injection impact mill (here, the additional amount of dry gas outside the gas-injection impact mill is the impact type) Has a higher temperature than the gas fed into the mill); And D) partially depolymerizing the cellulose derivative after contacting the cellulose derivative with a dry gas in step C).

Another aspect of the invention provides an uncompacted bulk density of at least 370 g/l; A Carr Index of 20 or less; A viscosity of 1.2 to 200 mPa·s, measured according to DIN 51562-1:1999-01 as a 2% by weight solution in water at 20° C.; And a particulate cellulose derivative having a color of 40 or less APHA color units, measured in 2% by weight aqueous solution at 20° C. according to ASTM D1209-05 (2011).

Another aspect of the invention is an aqueous composition prepared by blending water, the aforementioned particulate cellulose derivative and one or more optional additives.

Another aspect of the invention is a method of manufacturing a capsule, comprising the step of contacting the above-mentioned aqueous composition with a dipping pin.

Another aspect of the present invention is a method of coating a dosage form comprising the step of contacting the above-mentioned aqueous composition with the dosage form.

Surprisingly, a cellulose derivative having a lower color intensity in solution than when the partial depolymerization is carried out prior to drying and grinding steps A) to C) is obtained after drying and grinding steps A) to C) described above. It has been found to be obtained when subjected to partial depolymerization.

1 illustrates a flowchart of drying and grinding steps A) to C) of the method of the present invention.

The present invention relates to a method for producing a particulate cellulose derivative by drying and grinding a wet cellulose derivative.

The cellulose derivatives used in the method are generally soluble or at least soakable in a solvent, preferably water. These include one or more substituents, preferably hydroxyethyl, hydroxypropyl, hydroxybutyl, methyl, ethyl, propyl, dihydroxypropyl, carboxymethyl, sulfoethyl, hydrophobic long-chain branched and unbranched alkyl groups, hydrophobic long-chain branches and Unbranched alkyl aryl groups or aryl alkyl groups, cationic groups, acetate, propionate, butyrate, lactate, nitrate or sulfate type substituents, some of which groups, such as hydroxyethyl, Hydroxypropyl, hydroxybutyl, dihydroxypropyl and lactate can form grafts. Substituents of celluloses according to the invention are not limited to these groups.

Preferred cellulose derivatives are cellulose esters or cellulose ethers. Useful cellulose ethers include, for example, carboxy-C ₁ -C ₃ -alkyl cellulose, such as carboxymethyl cellulose; Carboxy-C ₁ -C ₃ -alkyl hydroxy-C ₁ -C ₃ -alkyl cellulose, for example carboxymethyl hydroxyethyl cellulose.

The cellulose ether is preferably an alkyl cellulose, hydroxyalkyl cellulose or hydroxyalkyl alkylcellulose. This means that in the cellulose ether of the present invention, at least some of the hydroxyl groups of the anhydroglucose units are substituted by an alkoxyl group or a hydroxyalkoxyl group or a combination of an alkoxyl group and a hydroxyalkoxyl group. Typically one or two types of hydroxyalkoxyl groups are present in the cellulose ether. Preferably there is a single kind of hydroxyalkoxyl group, more preferably hydroxypropoxyl.

Particularly preferred cellulose ethers are cellulose ethers having a thermal flocculation point in water, such as methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, ethylhydroxy ethylcellulose, and hydroxypropyl cellulose. to be. The cellulose ether is preferably water soluble, i.e., has a water solubility of at least 1 g, more preferably at least 2 g, most preferably at least 5 g per 100 g of distilled water at 25°C and 1 atmosphere.

Preferred alkyl hydroxyalkyl celluloses including mixed alkyl hydroxyalkyl celluloses include hydroxyalkyl methylcelluloses such as hydroxyethyl methylcellulose, hydroxypropyl methylcellulose or hydroxybutyl methylcellulose; Or hydroxyalkyl ethyl cellulose, such as hydroxypropyl ethylcellulose, ethyl hydroxyethyl cellulose, ethyl hydroxypropyl cellulose or ethyl hydroxybutyl cellulose; Or ethyl hydroxypropyl methylcellulose, ethyl hydroxyethyl methylcellulose, hydroxyethyl hydroxypropyl methylcellulose, or alkoxy hydroxyethyl hydroxypropyl cellulose, and the alkoxy group is linear or branched and has 2 to 8 carbon atoms. Preferred hydroxyalkyl celluloses include hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxybutyl cellulose; Or mixed hydroxylyl cellulose, such as hydroxyethyl hydroxypropyl cellulose.

Hydroxyalkyl alkylcellulose is preferred, hydroxyalkyl methylcellulose is more preferred, and hydroxypropyl methylcellulose is most preferred, which has MS (hydroxyalkoxyl) and DS (alkoxyl) described below. The degree of substitution of the hydroxyl group of the anhydroglucose unit by the hydroxyalkoxyl group is indicated by the molar substitution of the hydroxyalkoxyl groups, MS (hydroxyalkoxyl). MS (hydroxyalkoxyl) is the average number of moles of hydroxyalkoxyl groups per anhydroglucose unit in the esterified cellulose ether. It is understood that during the hydroxyalkylation reaction, the hydroxyl group of the hydroxyalkoxyl group bonded to the cellulose backbone can be further etherified by an alkylating agent, for example a methylating agent, and/or a hydroxyalkylating agent. A number of subsequent hydroxyalkylation etherification reactions to the same carbon atom position of the anhydroglucose unit yield side chains, wherein a plurality of hydroxyalkoxyl groups are covalently bonded to each other by ether bonds, and each side chain as a whole A hydroxyalkoxyl substituent is formed on the cellulose backbone. Thus, the term "hydroxyalkoxyl group" should be interpreted in the context of MS (hydroxyalkoxyl) as relating to a hydroxyalkoxyl group as a constituent unit of a hydroxyalkoxyl substituent, which as outlined above It contains a hydroxyalkoxyl group or side chain, wherein two or more hydroxyalkoxy units are covalently bonded to each other by an ether bond. Within this definition it is important that the terminal hydroxyl groups of the hydroxyalkoxyl substituents may or may not be further alkylated, for example methylated; Both alkylated hydroxyalkoxyl substituents and non-alkylated hydroxyalkoxyl substituents are included for the measurement of MS (hydroxyalkoxyl).

The hydroxyalkyl alkylcellulose generally has a molar substitution of the hydroxyalkoxyl group in the range of 0.05 to 1.00, preferably 0.08 to 0.90, more preferably 0.12 to 0.70, most preferably 0.15 to 0.60, especially 0.20 to 0.50. Have as The average number of hydroxyl groups substituted by alkoxyl groups per anhydroglucose unit, for example methoxyl groups, is referred to as the degree of substitution of the alkoxyl group, DS (alkoxyl). In the definition of DS provided above, the term "hydroxyl group substituted by an alkoxy group" refers to an alkylated hydroxyl group bonded directly to a carbon atom of the cellulose backbone as well as an alkylated hydroxyalkoxyl substituent bonded to the cellulose backbone. It is understood within the present invention to include hydroxyl groups. The hydroxyalkyl alkylcelluloses according to the invention preferably have a DS (alkoxyl) in the range of 1.0 to 2.5, more preferably 1.1 to 2.4, most preferably 1.2 to 2.2, in particular 1.6 to 2.05. Most preferably the cellulose ether has a DS (methoxyl) within the range indicated above for DS (alkoxyl) and MS (hydroxypropoxyl) or MS within the range indicated above for MS (hydroxyalkoxyl) Hydroxypropyl methylcellulose or hydroxyethyl methylcellulose with (hydroxyethoxyl). The degree of substitution of the alkoxyl group and the degree of molar substitution of the hydroxyalkoxyl group can be determined by Zeisel cleavage of cellulose ether with hydrogen iodide followed by quantitative gas chromatography analysis [see: G. Bartelmus and R. Ketterer, Z. Anal. Chem., 286 (1977) 161-190].

A preferred alkyl cellulose is methylcellulose. The average number of hydroxyl groups substituted by methoxyl groups per anhydroglucose unit is referred to as the degree of substitution (DS) of the methoxyl groups. Methylcellulose preferably has a DS of 1.20 to 2.25, more preferably 1.25 to 2.20, most preferably 1.40 to 2.10. The measurement of methoxyl (%) in methylcellulose is carried out according to the United States Pharmacopeia (USP 34). The values obtained are methoxyl (%). These values are then converted to the degree of substitution (DS) for the methoxyl substituent.

The viscosity of the cellulose derivative used in the method of the present invention, measured as a 2% by weight aqueous solution at 20° C. according to DIN 51562-1:1999-01, is generally 200 mPa·s or more, preferably 500 to 200,000 mPa·s, It is more preferably 500 to 100,000 mPa·s, most preferably 1000 to 80,000, and particularly 1000 to 60,000.

The preparation of cellulose derivatives, preferably cellulose ethers and cellulose esters, is known in the art. Typically, the manufacturing process is activated by treating the cellulose with an alkali metal hydroxide, reacting the cellulose thus treated with a derivatizing agent such as an etherification agent or an esterifying agent, and washing the cellulose derivative to remove by-products. Includes removal. After the washing step, the cellulose derivative generally has a moisture content of 25 to 60%, usually 40 to 55%, based on the total weight of the wet cellulose derivative. The preferred washing liquid may depend on the particular type of cellulose derivative, but the preferred washing liquid is generally water, isopropanol, acetone, methylethylketone or brine. A more preferred washing liquid is generally water or brine. The cellulose derivatives are generally washed at a temperature of 20 to 120°C, preferably 65 to 95°C. After washing the cellulose derivative and separating it from the washing liquid, a solvent-wet, preferably water-wet filter cake is obtained. The wet cellulose derivatives are usually obtained in the form of wet granules, wet lumps and/or wet pastes.

According to one aspect of the invention, the cellulose derivative is obtained by separating the cellulose derivative from a suspension in its liquid (eg water) and then performing the process of the invention. A suspension of particles in the liquid can occur by preparing and washing the cellulose derivative as described above. Separation of the cellulose derivative from the suspension can be carried out in a known manner such as centrifugation.

According to another aspect of the present invention, a dry cellulose derivative and a liquid (e.g., water) can be mixed at a desired moisture content in a compounder, and the wet cellulose derivative thus obtained can be followed by the method of the present invention. Treat it as an enemy.

A great advantage of the method of the invention is that it is possible to obtain cold water dispersible cellulose derivatives without mixing a significant amount of the surface-treating additive with the cellulose derivative and liquid (eg water). Thus, according to a preferred embodiment of the present invention, not significant amounts of surface-treating additives are added to the cellulose derivative. By "significant amount of surface-treating additive" is meant an amount that does not significantly change the surface properties and in particular the cold water dispersibility of the cellulose derivative. A surface-treating additive of preferably 1% or less, more preferably 0.5% or less, most preferably 0.2% or less, in particular 0%, based on the dry weight of the cellulose derivative is added to the cellulose derivative. Surface-treatment additives include, for example, surfactants such as sorbitol or lauryl sulfate; ester; Salts such as KCl, phosphate, nitrate or sulfate; Or sugars such as lactose, fructose, glucose, sucrose, or maltodextrin; Or a low molecular weight polymer such as polyethylene glycol or propylene glycol. The compounder preferably allows thorough and strong mixing. Useful compounders are, for example, granulators, kneaders, extruders, presses or roller mills, wherein the mixture of the cellulose derivative and the liquid is subjected to shearing and compounding (e.g., twin-screw ) By a compounder). Not only co-rotating but also reversing machines are suitable. As in the case of a twin-screw compounder, a so-called divided trough kneader having two horizontally arranged agitator blades that engage deeply with each other to perform mutual stripping action is particularly suitable. A suitable single shaft continuous kneader is the so-called Reflector® compounder (manufacturer: Lipp), a modular high-performance mixer consisting of a multi-part heating and cooling mixing cylinder and a one-side mounted blade mixer. Germany-based). Also suitable are so-called pinned cylinder extruders or Stiftconvert® extruders (manufacturer: Berstorff, Germany). In order to prevent the kneaded material from rotating with the shaft, the pins inserted into the housing act alternately. Kneader mixers (manufacturer: Fima, Germany) with so-called double-blade sigma stirrers with horizontal assembly are particularly suitable. The blades operate at different speeds, and the direction of their rotation can be reversed. Stirring vessels with vertically arranged mixer shafts are also provided if suitable flow baffles are mounted on the vessel wall to prevent the kneaded material from rotating with the stirrer shaft, and in this way the kneaded material is imparted a strong mixing action. , Suitable (manufacturer: Bayer AG). Also suitable are double-wall mixing vessels with a planetary stirrer and an in-line homogenizer.

In step A) of the process and method of the present invention, a cellulose derivative having a moisture content of 25 to 95%, based on the total weight of the wet polysaccharide derivative, is provided. The preferable lower limits of the moisture content are 30%, 35% and 38%, respectively. The preferred upper limits of the moisture content are 80%, 70% and 60%, respectively. Most preferably, the moisture content is 40 to 50%. The moisture content can be adjusted by adding a liquid such as water, isopropanol, acetone, methylethylketone or brine. Most preferably, water is used. The amount of liquid added to the water-soluble cellulose derivative must be adjusted for the moisture content that the cellulose derivative already has. The moisture content can be measured by ASTM method D-2363-79 (reapproved in 1989). The wet cellulose derivative in step A) preferably does not contain a significant amount of surface-treating additives (e.g., surface-treating additives described above) that remain on the cellulose derivative upon drying of the cellulose derivative. Preferably, the cellulose derivative comprises 1% or less, more preferably 0.5% or less, most preferably 0.2% or less of a surface-treating additive, based on the dry weight of the cellulose derivative, and in particular surface- Contains no treatment additives. It should be understood that any residual amount of by-products (eg sodium hydrochloride) from the preparation of the cellulose derivative is not included in the term "surface-treatment additive".

The temperature of the cellulose derivative before drying and grinding is preferably controlled within the range of 5 to 60°C, more preferably 5 to 45°C, most preferably 10 to 40°C, particularly 10 to 30°C, and is optionally changed or controlled. do. When a liquid such as water is added to the cellulose derivative before drying and grinding, the temperature of the cellulose derivative before drying and grinding preferably controls the temperature of the added liquid and/or the jacket temperature of the compounder and optionally It is controlled by changing or adjusting and is arbitrarily changed or adjusted.

Cellulose derivatives having a moisture content of 25 to 95% are usually in the form of wet granules, wet lumps and/or wet pastes. In step B), it is pulverized and partially dried in a gas-injection impact mill, preferably an air-injection impact mill, wherein the cellulose derivative is subjected to impact and/or shear stress. Preferred gas-injection impact mills are Ultra Rotor mills (Altenberger Maschinen Yeckering, Germany) or Turbofiner PLM mills (PALLMANN Maschinenfabrik GmbH & Co.KG), Germany )to be. Gas classifier mills, such as the Hosokawa Alpine air classifier mill (GPS Circoplex Hosokawa Micron Ltd. (ZPS Circoplex Hosokawa Micron Ltd., Cheshire, UK) are also useful gas-injection impact mills. Drying is usually achieved by the combination of gas and mechanical energy. Air or nitrogen gas can be used. In the method of the present invention, the gas supplied into the impact mill has a temperature of 100° C. or less, preferably 75° C. or less, and more preferably 50° C. or less. Typically, the gas supplied into the impact mill has a temperature of 10°C or higher, preferably 20°C or higher, and more preferably 30°C or higher. The gas stream having the above-mentioned temperature can be generated in a variety of ways. In one aspect of the present invention, a fresh gas stream having a desired temperature can be fed into the percussion mill. In another aspect of the invention, a recycle gas stream having the desired temperature is fed into the percussion mill. For example, the gas stream can be separated from the ground and dried cellulose derivative obtained in step C), as described further below, and the obtained solid-free gas stream or part thereof, for example , It can be cooled in a cooling system using water as a coolant. The obtained cooled gas stream can be fed into the mill. Alternatively, the entire amount of the cooled gas may be reheated, for example in a natural gas burner. In order to bring the reheated gas to a target temperature for feeding into the impact mill, a separate cooling gas stream may be combined with the hot gas stream before supplying the gas stream into the mill. The gas and wet product streams are generally supplied into the mill through separate inlets, typically gas is supplied from the base and the wet product is supplied from the side inlet through a feed screw system connected to the mill. do. In one aspect of step B) of the method, the wet cellulose derivative and gas are 10 to 90 m 3 /kg, more preferably 20 to 50 m 3 /kg of the cellulose derivative, based on the dry weight of the cellulose derivative. It is fed into the gas-injection impact mill at a rate. The circumferential velocity of the gas-injection impact mill is preferably 100 m/s or less. More preferably, the gas-injected impact mill operates in such a way that its circumferential velocity is in the range of 30 to 100 m/s, most preferably 35 to 80 m/s.

Essential features of the method of the present invention are that in step B) of the method the wet cellulose derivative is pulverized but only partially dried, and in step C) of the method the pulverized and partially dried cellulose derivative is converted to the gas- It is said to be in contact with an additional amount of dry gas outside the injection impact mill. Preferably, the ratio of the flow of gas in the gas-injection impact mill in step B) and the flow of the additional amount of dry gas in step C), i.e. (gas flow in step B)/(addition in step C) Gas flow) is 1:10 to 8:1, preferably 1:5 to 3:1, more preferably 1:3 to 2:1, most preferably 1:2 to 1:1, especially 1: 1.5 to 1:1. The term “additional amount of dry gas” as used herein refers to dry gas that is not supplied into the gas-injection impact mill. The person skilled in the art knows how to achieve only partial drying in step B). For example, it is possible to determine the gas stream required to essentially dry the cellulose derivative in the gas-injection impact mill at given process parameters (e.g., gas temperature and moisture content and temperature of the wet cellulose derivative). Incomplete drying in step B) results in an amount of gas that is less than the amount of gas required to dry and grind the cellulose derivatives to essentially dry products in the gas-injection impact mill, i.e. This can be achieved by supplying a smaller amount of gas per unit of cellulose derivative to be ground and dried into the gas-injection impact mill. In a preferred aspect of the present invention, the gas stream used to dry the cellulose derivative is divided into two streams through a slide valve, wherein the first gas stream is fed into the gas-injection impact mill, and the second gas The stream is brought into contact with the ground and partially dried cellulose derivative exiting the impact mill. Additionally, in step C) an additional amount of dry gas (i.e., the second gas stream) used outside the gas-injection impact mill is supplied into the impact mill (i.e., the first gas stream). It has been found that with higher temperatures, particulate cellulose derivatives of improved flowability and/or cold water dispersibility can be obtained. Preferably, the additional amount of dry gas outside the gas-injection impact mill is at least 70° C. higher, more preferably 100 to 220° C. higher than the gas supplied into the impact mill, or most preferably Has a higher temperature of 100 to 180°C. The temperature of the additional amount of dry gas outside the gas-injection impact mill is preferably 80 to 340°C, more preferably 100 to 220°C, and most preferably 125 to 210°C. The flow of the dry gas outside the gas-injection impact mill is preferably from 20 to 100 m 3 /kg, more preferably 25, based on the dry weight of the cellulose derivative in the gas-injection impact mill. To 80 m 3 /kg.

The first gas stream exiting the percussion mill may have a higher or lower temperature than the gas stream fed into the percussion mill. The temperature of the first gas stream exiting the impact mill depends on various factors such as the temperature, amount and moisture content of the wet cellulose derivative and the mechanical energy of the impact mill. The first gas stream exiting the impact mill can be partially or completely separated from the ground and partially dried cellulose derivative before the cellulose derivative contacts the second gas stream, but preferably the cellulose derivative is , When it comes into contact with the second gas stream, it is suspended in at least a portion or more preferably the entire amount of the gas stream exiting the gas-injection impact mill. The amount and temperature of the second gas stream (i.e., an additional amount of dry gas outside the gas-injection impact mill) is preferably the gas stream combined in step C), which is the agent exiting the impact mill. 1 gas stream and an additional amount of dry gas used in step C)) is at least 30° C. higher than the temperature of the first gas stream exiting the impact mill, or more preferably 35 to 100° C. It is chosen to have a higher, or most preferably 40 to 90° C. higher temperature.

In the drying step C) of the method of the present invention, the moisture content of the cellulose derivative is, based on the total weight of the wet cellulose derivative, usually 1 to 20%, preferably 2 to 10%, more preferably 3 to It decreases to 8%.

After step C), the pulverized and dried cellulose derivative particles are preferably separated from the gas flow in a separator arranged downstream of the gas-injection impact mill. The separator is preferably designed to perform gas classification, such as air classification. This can be, for example, a centrifuge such as a cyclone, or a filter separator such as a shifter. Alternatively, depending on the configuration of the gas-injection impact mill, gas classification may already occur in the gas-injection impact type mill. The gas flow separated from the cellulose derivative particles can be recycled and reused in steps B) and/or C) of the method of the invention. Alternatively, the gas flow separated from the cellulose derivative particles is not recycled and not reused in steps B) and C) of the method of the invention, and fresh gas from the environment is used in steps B) and/or C). .

The cellulose derivatives obtained after steps A) to C) of the process of the invention have an increased bulk density compared to the cellulose derivatives not treated by steps A) to C). The increased bulk density enables a larger loading of the reactor used in the subsequent partial depolymerization step D). After contacting the cellulose derivative with a dry gas in step C), the viscosity of the cellulose derivative measured as a 2% by weight solution in water at 20° C. according to DIN 51562-1:1999-01 is generally 200 mPa·s or more, It is preferably 500 to 200,000 mPa·s, more preferably 500 to 100,000 mPa·s, most preferably 1000 to 80,000, especially 1000 to 60,000.

In any sieving step between the drying step C) and the partial depolymerization step D) of the method of the present invention, the pulverized and dried cellulose derivative is 125 to 400 µm, preferably 160 to 355 µm, more preferably May be sieved through a sieve having a mesh size of 180 to 315 μm, most preferably 200 to 300 μm, for example, a mesh size of 220 μm. The optional sieving step may be performed after separating the pulverized and dried cellulose derivative from the gas flow in a separator (e.g., cyclone) arranged downstream of the gas-injection impact mill. Useful sieves are known in the art and are described in DIN 4188. A fine fraction having a particle size smaller than the mesh size of the sieve and a coarse fraction having a particle size larger than the mesh size of the sieve are obtained. These two fractions can be used individually as final products according to the invention which exhibit cold water dispersibility for both the fine fraction and the coarse fraction. Alternatively, in the method of the present invention, the pulverized and dried cellulose derivative is not sieved through a sieve. According to the method of the present invention, the cold water dispersible cellulose derivative can be prepared regardless of the constitution of the pulverized and dried cellulose derivative. The whole amount of the pulverized and dried cellulose derivative is water dispersible. This is a huge advantage, since the entire amount of the pulverized and dried cellulose derivative is useful and does not need to be recycled to the drying and pulverizing process and does not have to be used for other purposes where cold water dispersibility is less important.

The cellulose derivative is partially depolymerized in a further step D). Preferably, the partial depolymerization of the cellulose derivative is carried out in such a manner that the viscosity of the cellulose derivative is reduced by at least 10%, preferably at least 20%, more preferably at least 50%, based on the viscosity before the partial depolymerization. . After partial depolymerization, the viscosity of the cellulose derivative measured as a 2% by weight solution in water at 20° C. according to DIN 51562-1:1999-01 is generally 1.2 to 200 mPa·s, preferably 2 to 100 mPa·s, more It is preferably 2.5 to 50 mPa·s, particularly 3 to 30 mPa·s. Partial depolymerization processes are generally known in the art.

The cellulose derivative may be partially depolymerized in contact with an acid, preferably a strong acid. The amount of the acid is generally 0.1 to 5% by weight, based on the weight of the starting cellulose derivative. Preferred acids are hydrogen halides, such as hydrochloric acid. The acid may be in the form of a gas, for example as described in European patent application EP 1,141,029, or in the form of an aqueous solution as described, for example in European patent application EP 210,917. When the acid is used in the form of an aqueous solution, the amount of water is generally 3 to 8% by weight, based on the weight of the cellulose derivative used as a starting material. The partial depolymerization is generally carried out at a temperature in the range of 50 to 130°C, preferably 60 to 110°C, more preferably 65 to 90°C.

Alternatively, the cellulose derivative may be partially depolymerized in contact with an oxidizing agent. Examples of suitable oxidizing agents are ozone, peroxide, halite, halite, perhalate, hypohalite and perborate, and hydrogen peroxide. Preferred oxidizing agents include alkali metal chlorite, alkali metal chlorate such as potassium chlorate or sodium chlorate, alkali metal perchlorate, alkali metal periodate, alkali metal hypobromite, alkali metal hypochlorite, alkali metal hypoiodate, alkali. Metal peroxide, and hydrogen peroxide. Sodium and potassium are preferred alkali metals. The amount of the oxidizing agent is generally 0.01 to 3% by weight, based on the starting cellulose derivative. The use of such oxidizing agents is described in US Pat. No. 4,316,982 and in the prior art discussed herein.

The acid and the oxidizing agent may be used separately or may be used in combination. Combining uses are described in European patent application EP 1,423,433. The method described above is useful for improving the flowability and/or cold water dispersibility of particulate cellulose derivatives.

The particulate cellulose derivatives prepared according to the method of the invention generally have an uncompacted bulk density of at least 370 g/l, preferably at least 400 g/l, more preferably even at least 430 g/l. Uncompacted bulk densities of 530 g/l or less, or even 600 g/l or less under optimal conditions are generally achieved. As used herein, the bulk density (BD) is the apparent volume to mass ratio of the taken material (so-called uncompacted bulk density), and also the tapped volume to mass ratio of the material taken (so-called tapped bulk density). density)). A useful procedure for measuring these bulk densities is described in United States Pharmacopeia 24, Test 616 "Bulk Density and Tapped Density", United States Pharmacopeia Convention, Inc., Rockville, Maryland, 1999.

The particulate cellulose derivative produced according to the method of the present invention generally has a Carr index of 20 or less, preferably 18 or less, more preferably 16 or less, and under optimal conditions of 15 or less. The minimum karr index is 1. The Carr's index of the particulate cellulose derivative is usually 5 or less, and more typically 8 or less. Carr's index C is an index of the compressibility of the powder. This is calculated by the following equation:

C = 100 * (BD compacted-BD un compacted) / BD compacted

Here, "BD compacted" is the compacted bulk density of the powder and "BD un compacted" is the un compacted bulk density of the powder. The Karr index is frequently used in pharmaceutical science as an indicator of the fluidity of a powder. A Karr index of 15 or less is considered an indicator of good liquidity [Kanig, Joseph L.; Lachman, Leon; Lieberman, Herbert A. (1986). The Theory and Practice of Industrial Pharmacy (3ed.). Philadelphia: Lea & Febiger].

The particulate cellulose derivative prepared according to the method of the present invention has excellent cold water dispersibility. "Cold water" means water at a temperature below room temperature, room temperature or slightly above room temperature, ie water at a temperature of generally 0 to 40°C, usually 5 to 30°C, more usually 10 to 25°C. Cold water dispersibility is measured as described in the examples. The criterion for poor cold water dispersibility or cold water dispersibility is visualized by the formation of agglomerates of cellulose derivatives in cold water. Clump formation strongly blocks the product from dissolving over time.

In addition, the method of the present invention is useful for preparing cellulose derivatives of a specific size and shape. The particle size and shape of the particulate cellulose derivative can be measured by a high-speed image analysis method that combines particle size and shape analysis of sample images. Image analysis methods for composite powders are described in W. Witt, U. Koehler, J. List, Current Limits of Particle Size and Shape Analysis with High Speed Image Analysis, PARTEC 2007. The high-speed image analysis system is commercially available as a dynamic image analysis (DIA) system QICPIC™ from Sympatec GmbH of Claustal-Zellerfeld, Germany. The high speed image analysis system is particularly useful for measuring the following dimensional parameters of particles:

EQPC : The EQPC of a particle is defined as the diameter of a circle having the same area as the projected area of the particle. For the purposes of the present invention, the median EQPC is the volume distribution average of all particles in a given sample of particulate cellulose derivative and is referred to as EQPC 50,3. The volume distribution is referred to by the number 3 after the comma. Median EQPC means that 50% of the EQPC of the particle distribution is smaller than a given value (unit: μm) and 50% is greater than a given value.

LEFI : Particle Length LEFI is defined as the longest direct path connecting the ends of the particle inside the contour of the particle. "Direct" means no loops or branches. For the purposes of the present invention, the intermediate LEFI is the volume distribution average of all particles in a given sample of the particulate cellulose derivative and is referred to as LEFI 50,3. The volume distribution is referred to by the number 3 after the comma. Median LEFI means that 50% of the LEFI of the particle distribution is smaller than a given value (in μm) and 50% is greater than a given value.

The particulate cellulose derivative prepared according to the method of the present invention is generally at least 50 μm, preferably at least 70 μm, and in some preferred embodiments of the present invention, an equivalent projected circle diameter (EQPC) (Equivalent Projected Circle Daimeter) of at least 100 μm. Has. The particulate cellulose derivative generally has an intermediate EQPC of 500 μm or less, preferably 400 μm or less, more preferably 300 μm or less, most preferably 200 μm or less.

The particulate cellulose derivatives prepared according to the method of the present invention generally have an intermediate LEFI of 50 to 600 μm, more preferably 80 to 500 μm and most preferably 100 to 400 μm.

In addition, by the method of the present invention in which the cellulose derivative undergoes a partial depolymerization step D) after the drying and grinding steps A) to C) as described above, the cellulose derivative having a lower color intensity in the solution is obtained in the drying and grinding step A A) to C) are obtained more than in a comparable method in which the partial depolymerization is carried out before. The particulate cellulose derivative prepared according to the method of the present invention is 40 or less APHA color units, preferably 38 or less APHA, measured as a 2 wt% solution in water at 20° C. according to ASTM D1209-05 (2011). Color units, most preferably 35 or less APHA color units. The particulate cellulose derivative prepared according to the method of the present invention has a color of generally 20 or more APHA color units, typically 25 or more APHA color units, measured as a 2% by weight solution in water at 20°C. To prepare a 2% by weight solution of the cellulose derivative in water at 20° C., the procedure described in the US Pharmacopoeia (USP 35, "Hypromellose", pages 3467-3469) is applied.

A preferred embodiment of carrying out steps A) to C) of the method of the invention is illustrated in FIG. 1, which, although described in more detail below, is an embodiment of the invention illustrated by FIG. I am not trying to limit the scope.

Description of Figure 1:

1 total gas stream

2 gas stream passing through the bypass

3 gas stream through gas injection impact mill

4 cooled gas stream

5 heated gas stream after burner

6 Temperature of gas stream prior to gas injection impact mill

7 Temperature of gas stream after gas injection impact mill, °C

8 combined gas stream

9 Gas stream before filter

10 Gas stream temperature before blower, °C

11 blower

12 burner

13 mil feed unit

14 gas injection impact mill

15 cyclone

16 filters

17 Washer/cooler

18 Wet Cellulose Derivatives

19 valve

20 product

The terms "after the burner", "after the blower", and the like, as used herein, refer to the direction of the gas stream and have meanings such as "downstream of the burner" and downstream of the blower. Blower 11 circulates air or preferably nitrogen through a mill circuit to provide a total gas stream 1 of 1000 to 2200 m 3 /h, preferably measured with a flow meter. do. After the blower 11, the total gas stream 1 can be divided into a cooled gas stream 4 and a gas stream passing through the burner 12. The heated gas stream 5 after the burner consists of a gas stream 3 passing through the gas injection impact mill 14 and a gas stream 2 passing through the bypass (this is outside the gas injection impact mill. Can be divided into an additional amount of (which acts as a drying gas). In one aspect of the invention, the total amount of heated gas stream 5 after the burner is fed as gas stream 2 passing through the bypass; This means that only the cooled gas stream 4 is fed to the gas injection impact mill 14 and the amount of cooled gas stream 4 corresponds to the amount of gas stream 3 flowing through the gas injection impact mill. Means. Examples of the present invention utilize this aspect. The moistened cellulose derivative 18 may be added via a mill feed unit 13 comprising a feed screw system to a gas injection impact mill 14. The temperature 6 of the gas stream 3 is measured prior to the gas injection impact mill. The temperature 7 of the gas stream after the gas injection impact mill is measured. After the junction of the gas stream 2 passing through the bypass and the gas stream 3 passing through the gas injection impact mill, the temperature of the combined gas stream 8 containing the pulverized cellulose derivative is measured. do. The conduit from the mill to the starting point of the cyclone 15 can be considered as a flash dryer. The combined gas stream 8 is fed to a cyclone 15, where substantially all of the cellulose derivative is separated from the gas stream, except for some residual amounts of fine particles (dust). The residual amount of dust is removed by the filter 16. The temperature of the gas stream 9 prior to filter 16 is measured after it exits the cyclone 15 and before entering the filter 16. The filtered gas stream is passed through a washer/cooler (17). The temperature (10) of the washed and cooled gas stream is measured; The washed and cooled gas stream corresponds to the total gas stream 1 circulated by the blower 11. The flow of the gas stream described above is controlled by valve 19. The design of each of these valves is not necessarily identical, but controls the temperature and volume of the gas stream. Product 20 is fed to a reactor suitable for carrying out the partial depolymerization step D) (not shown).

The present invention also provides: i) an uncompacted bulk density of at least 370 g/l, preferably at least 400 g/l, more preferably at least 430 g/l, ii) 20 or less, preferably 18 or less, more preferably 16 Hereinafter, in some embodiments of the invention, even a Carr index of less than 15, iii) 1.2 to 200 mPa·s, preferably 2.0, measured as a 2% by weight solution in water at 20° C. according to DIN 51562-1:1999-01. A viscosity of from to 100 mPa·s, more preferably from 2.5 to 50 mPa·s, in particular from 3 to 30 mPa·s, and iv) 40, measured as a 2% by weight solution in water at 20° C. according to ASTM D1209-05 (2011). It relates to a particulate cellulose derivative having a color of the following APHA color units, preferably 38 or less APHA color units, more preferably 35 or less APHA color units. The particulate cellulose derivatives of the present invention typically have an uncompacted bulk density of 600 g/l or less, more typically 550 g/l or less, and most typically 510 g/l or less.

The Carr's index of the particulate cellulose derivative is usually 8 or more, more typically 10 or more, and most usually 12 or more. The particulate cellulose derivative generally has a color of 20 or more APHA color units, typically 25 or more APHA color units.

The particulate cellulose derivatives of the present invention generally have a median equivalent projection circle diameter (EQPC) of at least 50 μm, preferably at least 70 μm, and in some preferred embodiments of the invention at least 100 μm. The particulate cellulose derivative generally has an intermediate EQPC of 500 μm or less, preferably 400 μm or less, more preferably 300 μm or less, most preferably 200 μm or less. The particulate cellulose derivatives of the present invention generally have an intermediate LEFI of 50 to 600 μm, more preferably 80 to 500 μm, and most preferably 100 to 400 μm.

The particulate cellulose derivatives prepared according to the method of the invention and the novel particulate cellulose derivatives of the invention are useful in a number of applications where the excellent cold water dispersibility of the particulate cellulose derivative is advantageous. For example, the particulate cellulose derivatives are useful in pharmaceutical applications, preferably in liquid suspensions comprising cellulose derivatives and medicaments, or in aqueous solutions of the particulate cellulose derivatives for the preparation of hard shell capsules.

Another aspect of the invention is an aqueous composition prepared by blending water, the particulate cellulose derivative of the invention and one or more optional additives. Preferably, water, the particulate cellulose derivative of the invention and one or more optional additives, the composition comprises the cellulose derivative of the invention, based on the total weight of the aqueous composition, preferably 5 to 40%, more preferably It is blended in an amount such that it contains 10 to 30%. This aqueous composition is particularly useful for the preparation of capsules or dosage forms of coatings. Any additives such as colorants, flavor and taste improvers, antioxidants, plasticizers and surfactants may be incorporated into the composition. For example, when manufacturing capsules, water-soluble food dyes or natural dyes such as red oxide can be used as colorants; Ti0 ₂ can be used as a masking agent; Polyethylene glycol, polypropylene glycol, sorbitol or glycerin can be used as a plasticizer or as a surfactant to improve the flexibility of the capsule film. Particularly useful additives for coatings in solid form are monolayer film plasticizers, solid-load enhancers, secondary cellulose derivatives, preferably secondary cellulose ethers, surfactants, lubricants, brighteners, pigments, anti-tack agents, lubricants, opacifiers, colorants and Any combination of these.

In one aspect of the present invention, the aqueous composition is used to coat a dosage form such as a tablet, granule, pellet, dragee, lozenge, suppository, pessary or implantable dosage form to form a coated composition. I can. Preferred dosage forms are pharmaceutical dosage forms, nutritional supplements or agricultural dosage forms.

In another aspect of the present invention, the aqueous composition can be used in the manufacture of capsules. One method for making capsules is the "hot-pin mothod". The method preferably comprises the steps of (a) providing the above-mentioned aqueous composition, (b) preheating the dipping pins so that when they are immersed in the aqueous composition they are at a temperature above the gelling temperature of the aqueous composition, ( c) immersing the preheated dipping pins in an aqueous composition maintained at a temperature below its gelling temperature, (d) removing the dipping pins from the aqueous composition to obtain a film over the dipping pins and ( e) drying the film on the dipping pins at a temperature equal to or higher than the gelling temperature of the aqueous composition to obtain a molded capsule shell on the pins. The hot-pin method used to prepare capsules from aqueous compositions of cellulose ethers is described in detail in International Patent Publication No. WO 2008/050209.

Another method for making capsules is the "cold-pin method". In this method, the above-mentioned aqueous composition further comprises a gelling agent, such as carrageenan, pectin, gellan gum, or another sequestering or gelling aid, such as potassium, magnesium, ammonium or calcium ions. . In the cooling-pin method, the fins are generally maintained at room temperature, immersed in an aqueous composition maintained at a temperature above the gelation temperature, preferably at a temperature of 45 to 60° C., and the dipping fins are taken out from the aqueous composition, and the A film is obtained on the dipping pins, and the film is dried on the dipping pins to obtain a molded capsule shell on the pins. The cooling-fin method used to prepare capsules from the above mentioned aqueous compositions is described in detail in European Patent Application EP 0 714 656 and US Patent 6,410,050.

Example

Unless otherwise indicated, all parts and percentages are by weight. In the examples the following test procedures are used.

Measurements of methoxyl (%) and hydroxypropyl (%) in hydroxypropyl methylcellulose (HPMC) were carried out according to the US Pharmacopoeia (USP 35, "Hypromellose", pages 3467-3469). The values obtained are methoxyl (%) and hydroxypropyl (%). These can subsequently be converted to the degree of substitution (DS) for the methyl substituent and the degree of molar substitution (MS) for the hydroxypropyl substituent.

The viscosity of the HPMC sample was measured as a 2.0 wt% solution in water at 20°C. A 2.0 wt% HPMC solution in water was prepared according to the US Pharmacopoeia (USP 35, "Hypromellose", pages 3467-3469) and then the Ubelode viscosity was measured according to DIN 51562-1:1999-01 (January 1999). Became.

The compacted bulk density and uncompacted bulk density of HPMC in particulate form were measured using a Hosokawa Power Characteristics Tester: Model PT-N, available from Hosokawa Micron, Osaka Prefecture, Japan.

Carr's index C is calculated by the following equation.

C = 100 * (BD compacted-BD un compacted) / BD compacted

Here, "BD compacted" is the compacted bulk density of the powder and "BD un compacted" is the un compacted bulk density of the powder.

Intermediate LEFI and Intermediate EQPC are the average volume distribution of LEFI and EQPC of all particles in a given sample of particulate cellulose derivative. Intermediate LEFI and Intermediate EQPC, referred to as LEFI 50,3 and EQPC 50,3 in Table 1 below, have an image analyzer (dry dispensor RODOS/L, inner diameter 4 mm and dry feeder VIBRI). /L and software WINDOX5, version 5.3.0 and M7 lens, is a high-speed image analyzer sensor QICIPIC manufactured by Sympatec, Germany).

Cold water dispersibility (CWD) and torque build-up reflecting viscosity, the build-up of the particulate cellulose derivative after 60 minutes was measured according to the following procedure: 250 ml of a jacketed glass container It is filled with 125ml of tap water at 20℃. The jacket of the constant container was maintained at 20°C by a thermostat. A torque measuring shaker device (Haake VT 550, Thermo Scientific, Karlsruhe, Germany) (a shaker equipped with two rectangular blades, each drilled into an 8 mm hole) was used for the measurement. . The shaker blades were mounted on opposite sides with a pitch of 10 degrees to the axis, completely covered with the liquid in the vessel, and 5 mm away from the vessel wall. The shaker was turned on at 250 rpm. With constant shaking, 10% by weight of cellulose ether was administered to one batch of the container containing water. The criterion for poor cold water stability was visualized by the clumping of cellulose ether in cold water, which produced irregular torque peaks. The formation of agglomerates strongly inhibits the dissolution of the cellulose derivative over time.

The APHA color unit was measured at 20° C. as a 2% by weight solution in water.

A 2.0% by weight solution of HPMC in water was prepared according to the US Pharmacopoeia (USP 35, "Hypromellose", pages 3467-3469) and the APHA color units were measured according to ASTM D1209-05 (2011).

Example 1 to 5: drying-grinding steps A) to C)

Water was added to dry the cellulose derivative using a commercially available continuous compounder having a heating and cooling jacket. The cellulose derivatives used as starting materials in Examples 1 to 5 contained a water content of 1%, a median equivalent projection circle diameter (EQPC 50,3) 81 μm, a median particle length (LEFI 50,3) 249 μm, and an uncompacted bulk density ( BD) 294 g/L, compacted bulk density (BD) 438 g/L, and hydroxypropyl methylcellulose (HPMC) having a Carr index of 33. HPMC had 29.3% methoxyl groups, 6.2% hydroxypropoxyl groups, and had a viscosity of 5200 mPa·s measured as a 2.0% by weight solution in water at 20°C. HPMC used as starting material is not soluble in cold water, which was visualized as agglomerates in the method described above to measure cold water dispersibility (CWD).

The compounder jacket was supplied with the fluid used to control the temperature of the HPMC prior to drying and grinding, as listed in Table 1. HPMC was fed continuously to the compounder at the feed rates listed in Table 1. Water at a temperature of about 5° C. was added continuously to the compounder. The moistened cellulose derivative 18 (HPCM in this example) was fed into the wheat feed unit 13 (Altenburger Maschinen Jaeckering GmbH, Ham Germany) via a transport belt. Transported in series. The mill feed unit was a vessel equipped with a vessel shaker with blades and a single auger screw. The bottom blade of the container shaker pressed the wet HPMC paste with a single auger screw mounted on the bottom of the container. The wet HPMC is in the side of the gas-injected impact mill 14 (Ultrarotor II "S" impact mill from Altenburger Maschinen Yeckering GmbH, Ham, Germany, between the first and second grinding stages). Directly, across a perforated plate, and pressed. The gas injection impact mill was mounted on seven grinding stages. The bottom five grinding stages were equipped with standard grinding bars. The grinding bars were not installed in the top two grinding stages. The inside of the mill jacket had a standard Altenburger corrugated fixed grinding plate.

The rotor of the impact mill was operated at the circumferential speeds listed in Table 1 below. A particular gas flow system used herein was a closed loop system that applied nitrogen as a gas. The gas flow system consisted of three separately controllable gas streams. This control operation was performed by sliding the valves to allow control of the amount of each gas stream. At the same time, the temperature of the gas stream can be controlled via a natural gas burner and via a gas cooling system using coolant as a coolant. The resulting gas temperatures of each of the gas streams are listed in Table 1 below. The flows of gas streams applied in Examples 1 to 5 are listed in Table 1 below and illustrated in Figure 1.

The conditions of steps A) to C) of the method of the present invention, and the characteristics of the particulate HPMC prepared in steps A) to C) of the method of the present invention are listed in Table 1 below.

In Examples 1 to 5, no lump formation could be detected. After 30 minutes the cellulose derivative was already completely dissolved and showed a constant torque and viscosity.

Example 1 to 5: parts Depolymerization Step D)

The samples produced in steps A) to C) of Examples 1 to 5 as described above were partially depolymerized by heating the powdery samples with gaseous hydrogen chloride at the times and temperatures listed in FIG. 2 below.

40 kg of HPMC was loaded into a jacketed blender (1000 L capacity). After purging with nitrogen gas, heating was started and continued until a constant jacket discharge temperature of 85°C was reached. Then, at 6 full revolutions of the jacketed blender per minute, 72 g of anhydrous hydrogen chloride gas were added within 1 minute. The reaction times listed above were carried out at 85° C. jacket discharge temperature and at 6 full revolutions of the jacketed blender per minute. The HCl gas was then removed by evacuation, the heating was stopped and the jacketed blender was cooled to 25° C. within 80 minutes. The product was neutralized by adding 83 g of sodium bicarbonate and mixing for 60 minutes at 25° C. with 6 full revolutions per minute.

compare Example A: Step D)

For comparison purposes, HPMC used as a starting material in steps A) to C) of Examples 1 to 5, and HPMC of Comparative Example A did not perform steps A) to C) before performing partial depolymerization step D). Except that it did not, it was partially depolymerized as described in step D) of Examples 1 to 5 above.

Since HPMC used as the starting material in steps A) to C) of Examples 1 to 5 has a water content of 1%, HPMC was wetted to 6.0% with water before the partial depolymerization step, starting from Comparative Example A. The moisture content used in the material was adjusted to the moisture content of Examples 1 to 5.

The conditions and results of the partial depolymerization process are listed in Table 2 below.

Comparative Example B (as in co-pending patent application PCT/US12/031112)

Steps A) to C) were carried out with HPMC having 28.4% methoxyl groups, 6% hydroxypropyl groups and having a viscosity of 4.3 mPa·s measured as a 2.0 wt% solution in water at 20°C. HPMC used as starting material is commercially available from Dow Chemical Company as Methocel™ F4 hydroxypropyl methylcellulose. This material is obtainable by partial depolymerization of a higher viscosity HPMC using anhydrous hydrogen chloride, as in step D) of the process of the invention.

The operating procedure of steps A) to C) was carried out in such a way as to obtain cold water dispersible particulate HPMC having an uncompacted bulk density and a compacted bulk density within the ranges obtained in Examples 1 to 5 for comparison purposes. While the grinding and partial drying process step B) can be effectively carried out with HPMC of 73-75% water content before grinding, the HPMC of Comparative Example B can be effectively carried out at 43% in terms of lower HPMC viscosity.

Thus, Comparative Example B represents a process in which the partial depolymerization step D) precedes the process steps A) to C) instead of sequentially performing steps A) to D) as in the method of the present invention.

Comparative substance C)

Compacted and uncompacted bulk density (BD), viscosity and APHA color units of the commercially available Methocel™ F4 hydroxypropyl methylcellulose used as starting material in Comparative Example B were measured, and Examples 1-5 and Comparative Example A And B, together with the same properties, are listed in Table 3 below.

In Examples 1 to 5 and Comparative Example A, the uncompacted and compacted bulk density (BD) and Carr's index were measured prior to partial depolymerization of the solid particles with gaseous HCl. The partial depolymerization does not significantly affect the uncompacted and compacted BD and Carr's index.

Comparing Examples 1 to 5 and Comparative Example B, surprisingly, the partial depolymerization step (step D) is after the dry-milling operation (steps A) to C), rather than when the partial depolymerization step precedes the dry-milling operation. When carried out, it is exemplified that a weaker solution color of cold water dispersible cellulose derivative is obtained.

Claims (15)

As a method of producing a particulate cellulose derivative,
A) providing a cellulose derivative having a moisture content of 25 to 95%, based on the total weight of the wet cellulose derivative;
B) grinding and partially drying the wet cellulose derivative in a gas-swept impact mill (here, the gas supplied into the impact mill has a temperature of 100°C or less) ;
C) contacting the pulverized and partially dried cellulose derivative with an additional amount of drying gas outside the gas-injection impact mill (here, an additional amount of dry gas outside the gas-injection impact mill) Has a higher temperature than the gas supplied into the impact mill); And
D) partially depolymerizing the cellulose derivative after contacting the cellulose derivative with a dry gas in step C).
A method for producing a particulate cellulose derivative comprising a. The method of claim 1, wherein the additional amount of dry gas outside the gas-injection impact mill has a temperature at least 70° C. higher than the gas supplied into the impact mill. The method according to claim 1, wherein the prepared particulate derivative is alkyl cellulose, hydroxyalkyl cellulose or hydroxyalkyl alkylcellulose. A particulate cellulose derivative which can be prepared by the method of any one of claims 1 to 3. As a method of improving the flowability and/or dispersibility of cold water of a particulate cellulose derivative,
A) providing a cellulose derivative having a moisture content of 25 to 95%, based on the total weight of the wet cellulose derivative;
B) grinding and partially drying the wet cellulose derivative in a gas-injection impact mill, wherein the gas supplied into the impact mill has a temperature of 100°C or less;
C) contacting the pulverized and partially dried cellulose derivative with an additional amount of dry gas outside the gas-injection impact mill (here, the additional amount of dry gas outside the gas-injection impact mill is the impact type) Has a higher temperature than the gas fed into the mill); And
D) partially depolymerizing the cellulose derivative after contacting the cellulose derivative with a dry gas in step C).
A method for improving the flowability and/or dispersibility of cold water of the particulate cellulose derivative comprising a. The method of claim 4,
i) an uncompacted bulk density of at least 370 g/l;
ii) a Carr index of 20 or less;
iii) a viscosity of 1.2 to 200 mPa·s measured according to DIN 51562-1:1999-01 as a 2% by weight solution in water at 20° C.; And
iv) Color of APHA color unit of 40 or less measured as a 2% by weight solution in water at 20°C according to ASTM D1209-05 (2011)
Having, particulate cellulose derivative. 7. The particulate cellulose derivative of claim 6, having a median Equivalent Projected Circle Diameter (EQPC) of at least 50 μm. An aqueous composition prepared by blending water, the particulate cellulose derivative of claim 6, and at least one additive selected from the group consisting of colorants, flavor and taste improvers, antioxidants, plasticizers and surfactants. A method of manufacturing a capsule comprising the step of contacting the aqueous composition of claim 8 with dipping pins. A method of coating a dosage form comprising the step of contacting the aqueous composition of claim 8 with a dosage form. An aqueous composition prepared by blending water, the particulate cellulose derivative of claim 7 and at least one additive selected from the group consisting of colorants, flavor and taste improvers, antioxidants, plasticizers and surfactants. delete delete delete delete

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